Updates From ASCO in Melanoma Immuno-Oncology. Adil Daud, MBBS University of California San Francisco San Francisco, California

Transcription

1 Updates From ASCO in Melanoma Immuno-Oncology Adil Daud, MBBS University of California San Francisco San Francisco, California

2 3-Year Overall Survival for Patients With Advanced Melanoma Treated With Pembrolizumab in KEYNOTE-001 Abstract 9503 Robert C, Ribas A, Hamid O, Daud A, Wolchok JD, Joshua AM, Hwu W-J, Weber JS, Gangadhar TC, Joseph R, Dronca R, Patnaik A, Zarour H, Kefford R, Hersey P, Li XN, Diede SJ, Ebbinghaus S, and Hodi FS

3 Patients, % Patients, % Incidence of Immune-Mediated AEs a % 9.6% Analysis Previous 1 Current Mean Exposure 7.7 months 11.4 months Grade % % 2.7% Hypothyroidism Hyperthyroidism Pneumonitis 2.3% 1.7% 0.6% 0.9% 0.5% 0.9% 1.4% Colitis Hepatitis Nephritis Uveitis 1. Ribas A et al. JAMA 2016;315: a Based on a list determined by the sponsor and regardless of attribution by the investigator. 1. Ribas A, et al. JAMA. 2016;315(15): a Based on a list determined by the sponsor and regardless of attribution by the investigator Robert C, et al. J Clin Oncol. 2016;34(suppl): Abstract 9503.

4 Overall Survival Overall urvival, % Total Overall Survival, % Overall Survival, % Pts, N Events, n (55%) Median (95% CI) 24.4 mo ( ) Time, months No. at risk 50% 40% Overall Survival, % Treatment naive a Pts, N Events, n (47%) Median (95% CI) 32.2 mo (27.2-NR) Time, months No. at risk 61% 45% a Excludes patients with ocular melanoma Analysis cutoff date: Sept 18, 2015 Robert C, et al. J Clin Oncol. 2016;34(suppl): Abstract 9503.

5 Overall Survival by Subgroups Patients, N Events, N Median, months (95% CI) Rate at 24 months Rate at 36 months a Total ( ) 50% 40% By pembrolizumab dose 2 mg/kg Q3W ( ) 49% 38% 10 mg/kg Q3W ( ) 49% 39% 10 mg/kg Q2W ( ) 52% 43% By previous ipilimumab Treated ( ) 46% 41% Naïve ( ) 54% 41% a Rate may not be reliable because of high rate of censoring after 24 months Analysis cutoff date: Sept 18, 2015 Robert C, et al. J Clin Oncol. 2016;34(suppl): Abstract 9503.

6 Progression-Free Survival a Progression-Free Survival, % Progression-Free Survival, % Progression-Free Survival, % Pts, N Total Total Events, n (74%) Median (95% CI) 4.9 mo ( ) Time, months No. at risk 28% 21% Progression-Free Survival, % Treatment naive Treatment Naive b b Pts, N Events, n (66%) Median (95% CI) 5.0 mo ( ) 36% 30% No. at risk Time, months a Assessed per RECIST v1.1 by independent central review b Excludes patients with ocular melanoma Analysis cutoff date: Sept 18, 2015 Robert C, et al. J Clin Oncol. 2016;34(suppl): Abstract 9503.

7 Response, % Response, % Duration of Response a % 57% Time, months No. at risk Median (range), months Ongoing Response b NR (1.3+ to 38.8+) 137 (66%) a Assessed per RECIST v1.1 by independent central review in patients with response, regardless of centrally evaluable disease at baseline. b Responders who were alive without disease progression or new anticancer therapy. Analysis cutoff date: Sep 18, a Assessed per RECIST v1.1 by independent central review in patients with response, regardless of centrally evaluable disease at baseline. b Responders who were alive without disease progression or new anticancer therapy. Analysis cutoff date: Sept 18, Robert C, et al. J Clin Oncol. 2016;34(suppl): Abstract 9503.

8 ORR (95% CI), % ORR (95% CI), % Antitumor Activity (RECIST v1.1, Central Review a ) % 51% Previous analysis 1,b Current analysis c % 33% % 10% 0 Overall Overall Response Response Rate Rate Disease Control Rate Complete Complete Response Response 1. Ribas A et al. JAMA 2016;315: a Assessed in patients with measurable disease per RECIST v1.1 at baseline. b Analysis cutoff date: Sep 18, c Analysis cutoff date: Oct 18, Ribas A, et al. JAMA. 2016;315(15): a Assessed in patients with measurable disease per RECIST v1.1 at baseline b Analysis cutoff date: Sept 18, 2015 c Analysis cutoff date: Oct 18, 2014 Robert C, et al. J Clin Oncol. 2016;34(suppl): Abstract 9503.

9 Q1: Which of the following results were seen in patients who discontinued anti-pd-1 treatment after achieving a complete response? 1. 37% relapsed within 6 months of discontinuation 2. 5 patients died following disease progression 3. 14% restarted treatment 4. 97% of responses were maintained

10 Complete Responders: Disposition 85 (89%) remained in CR a 95 (15%) patients had CR per irrc by investigator review 18 (19%) remained on pembrolizumab 16 (17%) discontinued for AEs (n = 9), PD (n = 2), or other reason (n = 5) 61 (64%) stopped pembrolizumab for observation a Patient was alive and without disease progression Analysis cutoff date: Sept 18, 2015 Robert C, et al. J Clin Oncol. 2016;34(suppl): Abstract a Patient was alive and without disease progression. Analysis cutoff date: Sep 18, 2015.

11 Complete Responders Who Stopped Pembrolizumab for Observation (N = 61) 23 months 23 months Median time on treatment: 23 months (range, 8-44) Median time off treatment: 10 months Time on therapy Time to last scan Last dose Robert C, et al. J Clin Oncol. 2016;34(suppl): Abstract Time, months Total bar length represents the time to the last scan Analysis cutoff date: Sept. 18, 2015

12 3 months Complete Responders Who Stopped Pembrolizmab for Observation (N = 61) Median time to first response: 3 months (range, 0.5-8) Time on therapy Time to last scan Last dose Complete response Partial response Time, months Robert C, et al. J Clin Oncol. 2016;34(suppl): Abstract Total bar length represents the time to the last scan Analysis cutoff date: Sept. 18, 2015.

13 Complete Responders Who Stopped Pembrolizumab for Observation (N = 61) 13 months Median time to complete response (CR): 13 months (range, 3-33) Time on therapy Time to last scan Last dose Complete response Partial response Robert C, et al. J Clin Oncol. 2016;34(suppl): Abstract Time, months Total bar length represents the time to the last scan. Analysis cutoff date: Sept 18, 2015.

14 Complete Responders Who Stopped Pembrolizumab for Observation (N = 61) 1 year 2 years 3 years 59 (97%) of responses were maintained Time on therapy Time to last scan Last dose Complete response Partial response Robert C, et al. J Clin Oncol. 2016;34(suppl): Abstract Time, months Total bar length represents the time to the last scan Analysis cutoff date: Sept 18, 2015

15 Complete Responders Who Stopped for Pembrolizumab Observation (N = 61) 1 year 2 years 3 years 3 years Only 2 patients experienced disease progression Unconfirmed progression; patient remains follow-up in follow-up Confirmed progression; patient started started second second pembrolizumab pembrolizumab course course Time on therapy Time to last scan Last dose Complete response Partial response Progressive disease Robert C, et al. J Clin Oncol. 2016;34(suppl): Abstract Time, months Total bar length represents the time to the last scan Analysis cutoff date: Sept 18, 2015

16 Pembrolizumab Versus Ipilimumab for Advanced Melanoma: Final Overall Survival Analysis of KEYNOTE-006 Abstract 9504 Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, 1 Ella Lemelbaum Institute for Melanoma, Sheba Medical Center, Tel Hashomer, Israel; 2 University of California, Los Angeles, Los Angeles, CA; 3 Melanoma Institute Australia, The University of Sydney, Mater Hospital, and Royal North Shore Hospital, Sydney, Australia; 4 Hospital Clinic de Barcelona, Barcelona, Spain; 5 Aix Marseille University, Hôpital de la Timone, Marseille, France; 6 Université Lille, Centre Hospitalier Régional Universitaire de Lille, Lille, France; 7 University of California, San Francisco, San Francisco, CA; 8 Westmead and Blacktown Hospitals, Melanoma Institute Australia, and The University of Sydney, Sydney, Australia; 9Chris O Brien Lifehouse, Royal Prince Alfred Hospital, and Melanoma Institute Australia, Camperdown, Australia; 10 Sharett Institute of Oncology, Hadassah Hebrew Medical Center, Jerusalem, Israel; 11 Royal Marsden Hospital, London, UK; 12 University of Manchester and the Christie Zhou NHS Foundation H, Ebbinghaus Trust, Manchester, UK; 13 Universitair S, Ziekenhuis Ibrahim Brussel, Brussels, N, Robert Belgium; 14 Netherlands C Cancer Institute, Amsterdam, Netherlands; 15 Sunnybrook Health Sciences Center, Toronto, ON; 16 The Angeles Clinic and Research Institute, Los Angeles, CA; 17 Merck & Co., Inc., Kenilworth, NJ; 18 Gustave Roussy and Paris-Sud University, Villejuif, France

17 KEYNOTE-006 Study Design Patients Unresectable, stage III or IV melanoma 1 previous therapy, excluding anti CTLA-4, PD-1, or PD-L1 agents Known BRAF status a ECOG PS 0-1 No active brain metastases No serious autoimmune disease Stratification factors: ECOG PS (0 vs 1) Line of therapy (first vs second) PD-L1 status (positive b vs negative) R 1:1:1 Pembrolizumab 10 mg/kg IV q 2 weeks for 2 years Pembrolizumab 10 mg/kg IV q 3 weeks for 2 years Ipilimumab 3 mg/kg IV q 3 weeks x 4 doses Primary endpoints: PFS and OS Secondary endpoints: Overall response rate (ORR), duration of response (DoR), safety ECOG PS, Eastern Cooperative Oncology Group performance status; PD-L1, programmed death-ligand 1 a Prior anti-braf targeted therapy was not required for patients with normal LDH levels and no clinically significant tumor-related symptoms or evidence of rapidly progressing disease. b Defined as 1% staining in tumor and adjacent immune cells as assessed by IHC (22C3 antibody). National Institutes of Health. Available at: Accessed June 5, Schachter J, et al. J Clin Oncol. 2016;34(Suppl): Abstract 9504.

18 Post Study Antineoplastic Therapy: Anti CTLA-4, PD-1, and PD-L1 Agents Therapy a Pembrolizumab q 2 w N = 278 Pembrolizumab q 3 w N = 277 Ipilimumab N = 256 Anti CTLA-4 69 (25%) 60 (22%) 11 (4%) Anti PD-1 8 (3%) 11 (4%) 76 (30%) Anti PD-L1 1 (<1%) 2 (<1%) 2 (<1%) Anti CLTA-4 + anti PD (<1%) 1 (<1%) a Patients may have received 1 post study therapy. Final analysis data cutoff date: Dec 3, Schachter J, et al. J Clin Oncol. 2016;34(Suppl): Abstract 9504.

19 Baseline Characteristics Characteristic Pembrolizumab q 2 w N = 279 Pembrolizumab q 3 w N = 277 Ipilimumab N = 278 Age, median (range), years 61 (18-89) 63 (22-89) 62 (18-88) Men 161 (58%) 174 (63%) 162 (58%) ECOG PS (70%) 189 (68%) 188 (68%) Elevated LDH 81 (29%) 98 (35%) 91 (33%) BRAF V600 mutant 98 (35%) 97 (35%) 107 (38%) PD-L1 positive a 225 (81%) 221 (80%) 225 (81%) M1c disease 179 (64%) 189 (68%) 178 (64%) 1 previous therapy 96 (34%) 92 (33%) b 97 (35%) Schachter J, et al. J Clin Oncol. 2016;34(Suppl): Abstract a Defined as 1% staining in tumor and adjacent immune cells as assessed by IHC (22C3 antibody). b 1 patient had 2 lines of previous therapy. Final analysis data cutoff date: Dec 3, 2015.

20 OS, % Overall Survival Arm Events, n HR (95% CI) P No. at risk Pembro q 2 w Pembro q 3 w Ipi Time, months Schachter J, et al. J Clin Oncol. 2016;34(Suppl): Abstract % 68% 59% Pembro q 2 w ( ) Pembro q 3 w ( ) Ipi % 55% 43% NR (22.1-NR) NR (23.5-NR) 16.0 ( ) Final analysis data cutoff date: Dec 3, 2015.

21 Overall Survival in Key Subgroups N Male 497 Female 337 Age 65 years 471 Age <65 years 363 ECOG PS ECOG PS Normal LDH 547 Elevated LDH 270 BRAF V600 wildtype 532 BRAF V600 mutant prior therapies prior therapy 284 PD-L1 positive 671 PD-L1 negative 150 BTS <median 359 BTS median BTS, baseline tumor size Schachter J, et al. J Clin Oncol. 2016;34(Suppl): Abstract a Includes patients with unknown BRAF V600 mutation status (n = 17). Pembrolizumab doses were pooled. Dotted vertical line represents HR in the total population. Final analysis data cutoff date: Dec 3, 2015.

22 PFS, % No. at risk Pembro q 2 w Pembro q 3 w Ipi Progression-Free Survival a 39% 38% 19% Time, months Arm Events, n HR (95% CI) P b Pembro q 2 w ( ) < Pembro q 3 w ( ) < Ipi % 28% 14% 5.6 ( ) 4.1 ( ) 2.8 ( ) Schachter J, et al. J Clin Oncol. 2016;34(Suppl): Abstract a Assessed per RECIST v1.1 by independent central review. b P values are nominal only because no statistical alpha was applied to the comparison at final analysis. Final analysis data cutoff date: Dec 3, 2015.

23 ORR, % O R R, % ORR at Each Analysis a % % 336.1% 6 % 336.1% 6 % 333.7% 3 % 332.9% 2 % 111.9% 1 % % 2.9 % 113.3% 3 % IA11 IA22 Final a l IA11 IA2 2 FFinal a l IA11 IA2 2 FFinal a l Pembrolizumab P e m b ro liz u m a b P e mpembrolizumab b u m a b Ip ilim Ipilimumab u m ab q 2 weeks q 3 weeks Q 2 W Q 3 W CRR PPR R PR, partial response Schachter J, et al. J Clin Oncol. 2016;34(Suppl): Abstract a Assessed per RECIST v1.1 by independent central review. Interim analysis 1 (IA1) data cutoff date: Sep 3, 2014 (median follow-up, 7.9 months). Interim analysis 2 (IA2) data cutoff date: Mar 3, 2015 (median follow-up, 13.8 months). Final analysis data cutoff date: Dec 3, 2015 (median follow-up, 22.9 months).

24 Response, % Duration of Response a Arm Responders, n Median (range), Months Ongoing Response b No. at risk Pembro q 2 w Pembro q 3 w Ipi 74.5% 79.0% 79.3% Pembro q 2 weeks 103 NR (1.8 to 22.8+) 69 (67%) Pembro q 3 weeks 100 NR (2.0 to 22.8+) 60 (60%) Ipi 37 NR (1.1+ to 23.8+) 23 (62%) Time, months 70.6% 67.6% 70.0% Schachter J, et al. J Clin Oncol. 2016;34(Suppl): Abstract a Assessed per RECIST v1.1 by independent central review. b Patients without progression, death, or new anticancer therapy. Final analysis data cutoff date: Dec 3, 2015.

25 Q2: The most common immune-related adverse event associated with pembrolizumab treatment is? 1. Hepatitis 2. Rash 3. Hypothyroidism 4. Colitis

26 Time on therapy, weeks Exposure and AE Summary Pembro q 2 w N = 278 Pembro q 3 w N = 277 Ipilimumab N = 256 Median (range) 28.1 ( ) 24.0 ( ) 9.0 ( ) Mean (SD) 44.6 (37.2) 41.7 (37.7) 7.2 (3.1) Treatment-related AEs a Any grade 229 (82%) 213 (77%) 190 (74%) Grade (17%) 46 (17%) 50 (20%) Led to death (grade 5) 1 (<1%) b 0 0 Led to discontinuation 19 (7%) 30 (11%) 23 (9%) a Not adjusted for study treatment exposure. b Sepsis. Final analysis data cutoff date: Dec 3, Schachter J, et al. J Clin Oncol. 2016;34(Suppl): Abstract 9504.

27 In c id e n c e, % In c id e n c e, % In c id e n c e, % Incidence, c e n c e, % Incidence of Immune-Mediated AEs a Pembro q 2 w Pembro q 3 w Ipi Grade Pembro Q2W q 2 W Pembro Q3W q 3 W Ipi Any A n y grade g r a d e 0 Grade GA rn ayd e GLed Lre a dto e L e d to tx 3-4 d/c d D is c o n t. T h y r o id 00 a b n o r m a litie s b T h y r o id C o litis a b n o r m a litie s b C o litis H e p a titis H e p a titis P n e u m o n itis P n e u m o n itis U v e itis U v e itis H y p o p h y s itis H y p o p h y s itis M y o s itis M y o s itis T 1 D M T 1 D M N e p h r itis N e p h r itis Tx d/c, treatment discontinuation Schachter J, et al. J Clin Oncol. 2016;34(Suppl): Abstract a Not adjusted for exposure. Immune-mediated AEs are based on a list of terms specified by the sponsor and were considered regardless of attribution by the investigator. Includes hyper- and hypothyroidism and thyroiditis. Final analysis data cutoff date: Dec 3, 2015.

28 KEYNOTE-006 Study of Pembrolizumab Versus Ipilimumab for Advanced Melanoma: Efficacy by PD-L1 Expression and Line of Therapy Poster Discussion 9513 Daud A, Blank C, Robert C, Puzanov I, Richtig E, Margolin KA, O Day S, Nyakas M, Lutzky J, Tarhini A, McWhirter E, Caglevic C, Mohr P, Millward M, Butler M, Zhou H, Emancipator K, Ebbinghaus S, Ibrahim N, Long GV

29 KEYNOTE-006 Study Design Patients Unresectable, stage III or IV melanoma 1 previous therapy, exluding anti CTLA-4, PD-1, or PD-L1 agents Stratification factors: ECOG PS (0 vs 1) Line of therapy (first vs second) PD-L1 status (positive a vs negative) R 1:1:1 Pembrolizumab 10 mg/kg IV Q2W for 24 months Pembrolizumab 10 mg/kg IV Q3W for 24 months Ipilimumab 3 mg/kg Q3W x 4 doses a Defined as membranous PD-L1 staining in 1% of tumor cells and adjacent immune cells. ClinicalTrials.gov Accessed July 13, Daud A, et al. J Clin Oncol. 2016;34(Suppl): Abstract 9513.

30 P F S, % P F S, % PFS by Line of Therapy Treatment Naive 1 Previous Therapy m o R a t e P e m b r o 41% Ip i 18% H R (9 5 % C I) ( ) m o R a t e P e m b r o 28% Ip i 15% H R (9 5 % C I) ( ) N o. a t r is k T im e, m o n th s N o. a t r is k T im e, m o n th s Analysis cutoff date: March 3, Daud A, et al. J Clin Oncol. 2016;34(Suppl): Abstract 9513.

31 O S, % O S, % OS by Line of Therapy Treatment Naive 1 Previous Therapy m o R a t e H R (9 5 % C I) m o R a t e H R (9 5 % C I) P e m b r o 74% Ip i 59% ( ) P e m b r o 66% Ip i 56% ( ) N o. a t r is k T im e, m o n th s N o. a t r is k T im e, m o n th s Analysis cutoff date: March 3, Daud A, et al. J Clin Oncol. 2016;34(Suppl): Abstract 9513.

32 Q3: Which of the following is true regarding the results seen in PD-L1-negative patients in the Keynote-006 trial comparing pembrolizumab to ipilimumab? 1. PFS was longer in patients receiving ipilimumab 2. More patients responded to ipilimumab 3. OS was longer on pembrolizumab 4. OS was similar between the two arms

33 PFS and OS by PD-L1 IHC Score PFS OS N e g a tiv e IH C 0 (n = 5 7 ) IH C 1 (n = 9 3 ) N e g a tiv e IH C 0 (n = 5 7 ) IH C 1 (n = 9 3 ) IH C 2 (n = ) IH C 2 (n = ) P o s itiv e IH C 3 (n = ) IH C 4 (n = 8 7 ) P o s itiv e IH C 3 (n = ) IH C 4 (n = 8 7 ) IH C 5 (n = 7 5 ) IH C 5 (n = 7 5 ) 0.1 F a v o r s 1 F a v o r s 1 0 P e m b ro liz u m a b Ip ilim u m a b 0.1 F a v o r s 1 F a v o r s 1 0 P e m b ro liz u m a b Ip ilim u m a b H a z a r d R a tio H a z a r d R a tio Patients with unknown PD-L1 status were excluded. Dotted vertical lines represent the hazard ratio in the total population. Analysis cutoff date: March 3, Daud A, et al. J Clin Oncol. 2016;34(Suppl): Abstract 9513.

34 O R R, % ORR by PD-L1 IHC Score P e m b ro liz u m a b Ip ilim u m a b IH C 0 IH C 1 IH C 2 IH C 3 IH C 4 IH C 5 N e g a tiv e P o s itiv e Patients with unknown PD-L1 status were excluded. Dotted horizontal lines represent the ORR for pembrolizmab and ipilimumab in the total population. Analysis cutoff date: March 3, Daud A, et al. J Clin Oncol. 2016;34(Suppl): Abstract 9513.

35 Updated Results From a Phase III Trial of Nivolumab Combined With Ipilimumab in Treatment-Naïve Patients With Advanced Melanoma (Checkmate 067) Abstract 9505 Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob J-J, Cowey CL, Lao CD, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Haanen J, Maio M, McArthur G, Walker D, Jiang J, Corak C, Larkin J, Hodi FS

36 Q4: Which of the following was observed in a trial examining the combination of ipilimumab and nivolumab? 1. PD-L1-negative patients responded better to ipilimumab than the combination 2. 67% of BRAF-mutant patients responded to the ipilimumab and nivolumab combination 3. Patients older than 75 survived longer on single-agent nivolumab than the combination 4. Stable disease was achieved more frequently with nivolumab than ipilimumab

37 CA : Study Design CA : Study Design *Verified PD-L1 assay with 5% expression level was used for the stratification of patients; validated PD-L1 assay was used for efficacy analyses. **Patients could have been treated beyond progression under protocol-defined circumstances Wolchok JD, et al. J Clin Oncol. 2016;34(Suppl): Abstract 9505.

38 PFS (Intent-to-Treat Population) Progression-Free Survival (Intent-to-Treat Population) Database lock November 2015 Wolchok JD, et al. J Clin Oncol. 2016;34(Suppl): Abstract 9505.

39 Response to Treatment Response To Treatment *By RECIST v1.1. NR, not reached Database lock November 2015 Wolchok JD, et al. J Clin Oncol. 2016;34(Suppl): Abstract 9505.

40 PFS in Patient Subgroups (18-Month Follow-Up) PFS in Patient Subgroups (18 month follow-up) Wolchok JD, et al. J Clin Oncol. 2016;34(Suppl): Abstract 9505.

41 ORR in Patient Subgroups (18-Month Follow-Up) ORR in Patient Subgroups (18 month follow-up) Wolchok JD, et al. J Clin Oncol. 2016;34(Suppl): Abstract 9505.

42 PFS by Tumor PD-L1 Expression Progression-free Survival by Tumor PD-L1 Expression For the original PD-L2 PFS analysis, the descriptive hazard ratio comparing NIVO + IPI vs NIVO was 0.96, with a similar median PFS in both groups (14 months) Database lock November 2015 Wolchok JD, et al. J Clin Oncol. 2016;34(Suppl): Abstract 9505.

43 Response to Treatment by Tumor PD-L1 Expression* Response to Treatment by Tumor PD-L1 Expression* *Pretreatment tumor specimens were centrally assessed by PD-L1 immunohistochemistry (using a validated assay) Database lock November 2015 Wolchok JD, et al. J Clin Oncol. 2016;34(Suppl): Abstract 9505.

44 Overall Survival From an Open-label, Randomized, Phase II Study of Nivolumab Given Sequentially With Ipilimumab in Patients With Advanced Melanoma (CheckMate 064) Abstract 9517 Weber JS, Gibney G, Sullivan RJ, Sosman JA, Slingluff, Jr CL, Lawrence DP, Logan TF, Schuchter LM, Nair S, Buchbinder EI, Berghorn E, Ruisi M, Jiang J, Horak C, Hodi FS

45 Q5: Which of the following were observed in a phase II trial examining ipilimumab and nivolumab given in sequence? 1. The highest response rate was seen when ipilimumab was given before nivolumab 2. The highest response rate was seen when nivolumab was given before ipilimumab 3. The order in which the treatments were given did not impact response rate

46 Randomize CheckMate 064: Study Design Randomized, open-label, phase II study evaluating the safety and efficacy of two immune checkpoint inhibitors given sequentially with planned switch Induction Period 1 Induction Period 2 Continuation Period Cohort A N= ~70 Cohort B N= ~70 Week # 1 NIVO 3 mg/kg Q2W x 6 IPI 3 mg/kg Q3W x 4 2W 3W 13 IPI 3 mg/kg Q3W x 4 NIVO 3 mg/kg Q2W x 6 25 NIVO 3 mg/kg Q2W Until PD, unacceptable toxicity, or withdrawal of consent TA TA TA TA, tumor assessment;, biopsy timepoint; PD, progressive disease; Q2W, every 2 weeks Database lock November 13, 2015 Weber JS, et al. J Clin Oncol. 2016;34(suppl): Abstract 9517.

47 Study Objectives: NIVO IPI vs IPI NIVO Primary endpoint: To evaluate the incidence of treatment-related grade 3-5 AEs during the induction periods in both cohorts Secondary endpoints: Confirmed ORR at week 25 by modified RECIST v1.1* Progression rates at week 13 and week 25 Exploratory endpoints: Safety and tolerability during the different treatment periods Pharmacodynamic immune biomarkers OS Current analysis (Nov 2015 DBL): Best overall response (BOR), OS, objective response rate (ORR), and safety *Week 25 scan reflected back to baseline for determining response, with confirmation at Week 33 Weber JS, et al. J Clin Oncol. 2016;34(suppl): Abstract 9517.

48 Efficacy Summary Week 25 Entire Study Period* NIVO IPI (n = 68) IPI NIVO (n = 70) NIVO IPI (n = 68) IPI NIVO (n = 70) ORR, % (95% CI) 41.2 ( ) 20.0 ( ) 55.9 ( ) 31.4 ( ) Complete response, % Partial response, % Duration of OR, med (range) months NA ( ) NA (0 20.1) Deaths before or at Week 25 are counted as progression outcome * Assessed over whole study period by BOR using RECIST v1.1 Weber JS, et al. J Clin Oncol. 2016;34(suppl): Abstract 9517.

49 Reduction from Baseline in Target Lesion (%) Tumor Burden Change From Baseline Week 13 Week 25 Best Reduction Median Cohort A -27% Median Cohort B +10% Median Cohort A -50% Median Cohort B -17% Median Cohort A -66% Median Cohort B -37% Patients Patients Patients Confirmed responder; 30% reduction in tumor burden by RECIST v1.1; Truncated to 100% Weber JS, et al. J Clin Oncol. 2016;34(suppl): Abstract 9517.

50 Exploratory OS Analysis 12-mo OS rate = 76% 12-mo OS rate = 54% Events Median OS (95% CI) Cohort A 24/68 NA (23.7-NA) Cohort B 40/ ( ) Months Weber JS, et al. J Clin Oncol. 2016;34(suppl): Abstract 9517.

51 Pembrolizumab Plus Ipilimumab For Advanced Melanoma: Results of the KEYNOTE-029 Expansion Cohort Abstract 9506 Long GV, Atkinson V, Cebon JS, Jameson MB, Fitzharris BM, McNeil CM, Hill AG, Ribas A, Atkins MB, Thompson JA, Hwu W-J, Hodi FS, Menzies AM, Guminski AD, Kefford R, Shu X, Ebbinghaus S, Ibrahim N, Carlino MS

52 KEYNOTE-029: Study Design Dose Run-In (Part 1A) Patients Advanced MEL, 0 prior therapies OR Advanced RCC, 1 prior therapy Pembro 2 mg/kg Q3W up to 24 months + Ipi 1 mg/kg Q3W x 4 doses Tolerable based on DLT rate? No Yes Dose Expansion (Part 1B) Patients Advanced MEL 0 prior therapies No prior anti CTLA-4, PD-1, or PD-L1 ECOG PS 0 or 1 Stop development Combination tolerable based on DLT rate and AE profile 1,2 Primary end point: Safety Secondary end points: ORR, DOR, PFS, OS ClinicalTrials.gov. Accessed July 13, Atkins MA, et al. J Clin Oncol. 2016;34(suppl): Abstract Atkins MA, et al J Clin Oncol. 2015;33(suppl): Abstract Long GV, et al. J Clin Oncol. 2016;34(suppl): Abstract 9506.

53 AE Summary Category Treatment Related N = 153 Immune Mediated a N = 153 Any grade 145 (95%) 89 (58%) Grade (42%) 38 (25%) Led to death 0 0 Led to ipilimumab discontinuation only 16 (10%) 12 (8%) Led to pembrolizumab discontinuation only b 11 (7%) 6 (4%) Led to ipilimumab and pembrolizumab discontinuation 16 (10%) 11 (7%) a Regardless of attribution by the investigator. b After completion or discontinuation of ipilimumab. c Includes 1 patient who discontinued ipilimumab for colitis and later discontinued pembrolizumab for increased lipase. Data cutoff date: March 17, Long GV, et al. J Clin Oncol. 2016;34(suppl): Abstract 9506.

54 Treatment-Related AEs: Incidence >15% Event Any Grade N = 153 Grade 3-4 N = 153 Fatigue 70 (46%) 0 Pruritus 59 (39%) 0 Rash 59 (39%) 4 (3%) Diarrhea 36 (24%) 1 (<1%) Lipase increased 28 (18%) 22 (14%) Vitiligo 27 (18%) 0 Dry mouth 25 (16%) 0 Nausea 25 (16%) 0 Hypothyroidism 24 (16%) 0 Data cutoff date: March 17, Long GV, et al. J Clin Oncol. 2016;34(suppl): Abstract 9506.

55 Patients, % Immune-Mediated AEs: Incidence Any: 58% Grade 3-4: 25% Grade 1-2 Grade 3-4 a Includes grade 3 rash (n = 6), grade 3 drug reaction (n = 3), grade 3 pemphigoid (n = 1), and grade 2 exfoliative dermatitis (n = 1) Data cutoff date: March 17, Long GV, et al. J Clin Oncol. 2016;34(suppl): Abstract 9506.

56 Change From Baseline, % Best Change From Baseline in Tumor Size (RECIST v1.1, Investigator Review) Median change: 54.5% 81% ORR = 57% PD-L1 positive PD-L1 negative PD-L1 unknown Data cutoff date: March 17, Long GV, et al. J Clin Oncol. 2016;34(suppl): Abstract 9506.

57 ORR in Subgroups (RECIST v1.1, Independent Central Review) P D -L 1 p o s itiv e a (n = ) 5 7 % P D -L 1 n e g a tiv e (n = 2 4 ) T re a tm e n t n a iv e (n = ) P re v io u s ly tre a te d (n = 2 0 ) N o rm a l L D H (n = ) E le v a te d L D H (n = 3 7 ) B R A F V w ild ty p e (n = 9 0 ) B R A F V m u ta n t (n = 5 5 ) O R R, % a Positivity was defined as 1% staining in tumor and adjacent immune cells as assessed by IHC (22C3 antibody). All responses are confirmed. Data cutoff date: March 17, Long GV, et al. J Clin Oncol. 2016;34(suppl): Abstract 9506.

58 P F S, % Progression-Free Survival (RECIST v1.1, Independent Central Review) N o. a t ris k 70% T im e, m o n th s Events: 49 (32%) Median: NR (95% CI, 12.4 mo-nr) Median PFS not reached (95% CI, 12.4 mo to NR). Data cutoff date: March 17, Long GV, et al. J Clin Oncol. 2016;34(suppl): Abstract 9506.

59 O S, % Overall Survival N o. a t ris k 93% T im e, m o n th s Events: 16 (10%) Median: NR (95% CI, NR-NR) Data cutoff date: March 17, Long GV, et al. J Clin Oncol. 2016;34(suppl): Abstract 9506.

60 Efficacy Analysis of MASTERKEY-265 Phase 1b Study of Talimogene Laherparepvec and Pembrolizumab for Unresectable Stage IIIB-IV Melanoma Abstract 9568 Long GV, Dummer R, Ribas A, Puzanov I, VanderWalde A, Andtbacka RH, Michielin O, Olszanski AJ, Malvehy J, Cebon J, Fernandez E, Kirkwood JM, Gajewski TF, Gause C, Chen L, Gorski KS, Anderson AA, Kaufman DR, Chou J, and Hodi FS

61 Q6: Which of these statements best reflects your current opinion of the oncolytic virus T-VEC? 1. I have never used T-VEC but would if given the opportunity/appropriate patient 2. I have never used T-VEC and likely never will 3. I have never used T-VEC but might use it in combination with anti-pd-1/ctla-4 4. I have used T-VEC a few times 5. I use T-VEC frequently in my patients 6. I am not familiar enough with T-VEC to have an opinion

62 MASTERKEY-265 Phase 1b Study Schema N = 21 Unresectable stage IIIB to IVM1c melanoma Treatment naïve* Injectable lesions No clinically active brain metastasis No active or herpetic skin lesions or prior complications from herpetic infection Primary endpoint: Incidence of DLTs Key secondary endpoints: incidence of AEs, ORR by irrc, duration of response, PFS Talimogene laherparepvec (T-VEC) Up to 4 ml per treatment 1 st dose 10 5 PFU/mL 3 weeks later, 10 8 PFU/mL Q2W Week-5 T-VEC intralesional Pembrolizumab 200 mg IV Q2W Week-2 DLT Assessment Week-0 Window Week-6 Treatment until whichever occurs first Progressive disease per irrc Intolerance All injectable tumors disappeared (T-VEC only) 2 years S A F E T Y F O L L O W U P 30 (+7) days after end of treatment *No prior systemic anticancer treatment consisting of chemotherapy, immunotherapy, or targeted therapy given in a non-adjuvant setting DLT, dose-limiting toxicity; irrc, immune-related response criteria; IV, intravenous; PFU, plaque-forming unit Long GV, et al. J Clin Oncol. 2016;34(suppl): Abstract 9568.

63 Best Overall Response T-VEC + Pembrolizumab N = 21 Unconfirmed a Patients with a response, N Confirmed b Response rate, % (95% CI) 66.7 ( ) 57.1 ( ) Best overall response, N (%) Complete response 6 (28.6) 5 (23.8) Partial response 8 (38.1) 7 (33.3) Stable disease 1 (4.8) 3 (14.3) Progressive disease 6 (28.6) 6 (28.6) Disease control rate, c N (%) 15 (71.4) 15 (71.4) a Confirmation of complete response, partial response, or progressive disease by subsequent tumor assessment is not required b Tumor response evaluated per modified immune-related response criteria c Disease control rate includes stable disease, partial response, and complete response Long GV, et al. J Clin Oncol. 2016;34(suppl): Abstract 9568.

64 Best Change in Tumor Burden Safety analysis set includes all patients who received at least one dose of talimogene laherparepvec or pembrolizumab * No complete response due to presence of nonmeasurable lesions 17 patients were PD-L1 positive 2 patients were PD-L1 negative 2 patients were PD-L1 intermediate Long GV, et al. J Clin Oncol. 2016;34(suppl): Abstract 9568.

65 Change in Tumor Burden Over Time Long GV, et al. J Clin Oncol. 2016;34(suppl): Abstract 9568.

66 Lesion Level Response Injected Lesions Long GV, et al. J Clin Oncol. 2016;34(suppl): Abstract 9568.

67 Lesion Level Response Noninjected Nonvisceral Lesions Long GV, et al. J Clin Oncol. 2016;34(suppl): Abstract 9568.

68 Long GV, et al. J Clin Oncol. 2016;34(suppl): Abstract Lesion Level Response Noninjected Visceral Lesions

69 Circulating T-Cell Subsets and Expression of Activation Markers Each line color represents a different patient. Change from baseline fit to a linear mixed effects model considering visit, baseline, and patient ID as a random effect. P values (all are descriptive) on the plot are for change from baseline estimates compared to zero change. Long GV, et al. J Clin Oncol. 2016;34(suppl): Abstract 9568.

70 The KEYNOTE-001 study shows durability of response with a follow-up of 40 months KEYNOTE-006 final results indicate a PFS benefit in patients treated with pembrolizumab compared to treatment with ipilimumab The Checkmate-067 trial shows a PFS benefit in PD-L1 - patients treated with the combination of ipilimumab + nivolumab versus nivolumab alone Checkmate-064 results indicate that patients treated with nivolumab followed by ipilimumab have improved survival of patients treated with ipilimumab followed by nivolumab KEYNOTE-029 suggest that the combination of pembrolizumab + ipilimumab have the same response rate, but reduced toxicity when compared with the combination of ipilimumab + nivolumab